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The Journal of Neuroscience, June 15, 2000, 20(12):4686-4700
Long-Term rAAV-Mediated Gene Transfer of GDNF in the Rat Parkinson's Model: Intrastriatal But Not Intranigral Transduction Promotes Functional Regeneration in the Lesioned Nigrostriatal System
Deniz Kirik, Carl Rosenblad, Anders Björklund, and Ronald J. Mandel Wallenberg Neuroscience Center, Department of Physiological Sciences, Division of Neurobiology, Lund University, 223 62 Lund, Sweden
Previous studies have used recombinant adeno-associated viral (rAAV) vectors to deliver glial cell line-derived neurotrophic factor (GDNF) in the substantia nigra to protect the nigral dopamine (DA) neurons from 6-hydroxydopamine-induced damage. However, no regeneration or functional recovery was observed in these experiments. Here, we have used an rAAV-GDNF vector to express GDNF long-term (6 months) in either the nigral DA neurons themselves, in the striatal target cells, or in both of these structures. The results demonstrate that both nigral and striatal transduction provide significant protection of nigral DA neurons against the toxin-induced degeneration. However, only the rats receiving rAAV-GDNF in the striatum displayed behavioral recovery, accompanied by significant reinnervation of the lesioned striatum, which developed gradually over the first 4-5 months after the lesion. GDNF transgene expression was maintained at high levels throughout this period. These results provide evidence that rAAV is a highly efficient vector system for long-term expression of therapeutic proteins in the nigrostriatal system.
Key words: Parkinson's disease; 6-hydroxydopamine; glial cell line-derived neurotrophic factor; gene transfer; tyrosine hydroxylase; stepping; paw use; sensorimotor behavior; cell death; stereology
Copyright © 2000 Society for Neuroscience 0270-6474/00/20124686-15$05.00/0
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